ATP-dependent transporters

Diabetes Mellitus Insulin Receptor Glucose Transporters ATP-dependent K+Channel PPARs... 

Proteins that can flip phospholipids from one side of a bilayer to the other have also been identified in several tissues (Figure 9.11). Called flippases, these proteins reduce the half-time for phospholipid movement across a membrane from 10 days or more to a few minutes or less. Some of these systems may operate passively, with no required input of energy, but passive transport alone cannot establish or maintain asymmetric transverse lipid distributions. However, rapid phospholipid movement from one monolayer to the other occurs in an ATP-dependent manner in erythrocytes. Energy-dependent lipid flippase activity may be responsible for the creation and maintenance of transverse lipid asymmetries. 

The ABC-transporter superfamily represents a large group of transmembrane proteins. Members of this family are mainly involved in ATP-dependent transport processes across cellular membranes. These proteins are of special interest from a pharmacological point of... 

Chaperones bind to exposed hydrophobic surfaces of polypeptide substrates, and through either ATP-dependent or ATP-independent mechanisms facilitate the folding/assembly, intracellular transport, degradation, and activity of polypeptides. 

ATP-dependent K+ Channel Fatty Acid Transporters Nuclear Receptors Niacin... 

Breast cancer resistance protein (BCRP) is another ATP-dependent efflux transporter that confers resistance to a variety of anticancer agents, including... 

Acetylcholine is synthesised in nerve terminals from its precursor choline, which is not formed in the CNS but transported there in free form in the blood. It is found in many foods such as egg yolk, liver and vegetables although it is also produced in the liver and its brain concentration rises after meals. Choline is taken up into the cytoplasm by a high-affinity (Am = 1-5 pM), saturable, uptake which is Na+ and ATP dependent and while it does not appear to occur during the depolarisation produced by high concentrations of potassium it is increased by neuronal activity and is specific to cholinergic nerves. A separate low-affinity uptake, or diffusion (Am = 50 pM), which is linearly related to choline concentration and not saturable, is of less interest since it is not specific to cholinergic neurons. 

Uptake of noradrenaline into the vesicles depends on an electrochemical gradient driven by an excess of protons inside the vesicle core. This gradient is maintained by an ATP-dependent vesicular H+-triphosphatase. Uptake of one molecule of noradrenaline into the vesicle by the transporter is balanced by the counter-transport of two H+ ions (reviewed by Schuldiner 1998). It is thought that either binding or translocation of one H+ ion increases the affinity of the transporter for noradrenaline and that binding of the second H+ actually triggers its translocation. 

Solubilization of an active H,K-ATPase is also a prerequisite for reconstitution of the enzyme into liposomes. With these H,K-ATPase proteoliposomes it is then possible to study the transport characteristics of pure H,K-ATPase, without the interference of residual protein contamination that is usually present in native vesicular H,K-ATPase preparations. Rabon et al. [118] first reported the reconstitution of choleate or n-octylglucoside solubilized H,K-ATPase into phosphatidylcholine-cholesterol liposomes. The enzyme was reconstituted asymmetrically into the proteoliposomes with 70% of the pump molecules having the cytoplasmic side extravesicular. In the presence of intravesicular K, the proteoliposomes exhibited an Mg-ATP-dependent H transport, as monitored by acridine orange fluorescence quenching. Moreover, as seen with native H,K-ATPase vesicles, reconstituted H,K-... 

The Ca transport ATPase of sarcoplasmic reticulum is an intrinsic membrane protein of 110 kDa [8-11] that controls the distribution of intracellular Ca by ATP-dependent translocation of Ca " ions from the cytoplasm into the lumen of the sarcoplasmic reticulum [12-16],... 

Our discussion here will concentrate on the various forms of the Ca " transport ATPases that occur in the sarcoplasmic reticulum of muscle cells of diverse fiber types and in the endoplasmic reticulum of nonmuscle cells (SERCA). The structure of these enzymes will be compared with the Ca transport ATPases of surface membranes (PMCA) [3,29-32,34] and with other ATP-dependent ion pumps that transport Na, K, andH [46,50-52]. 

Chemical modification studies with fluorescein-5 -isothiocyanate support the proximity of Lys515 to the ATP binding site [98,113-117,212,339]. Fluorescein-5 -isothiocyanate stoichiometrically reacts with the Ca -ATPase in intact or solubilized sarcoplasmic reticulum at a mildly alkaline pH, causing inhibition of ATPase activity, ATP-dependent Ca transport, and the phosphorylation of the Ca " -ATPase by ATP the Ca uptake energized by acetylphosphate, carbamylphos-phate or j -nitrophenyl phosphate is only partially inhibited [113,114,212,339]. The reaction of -ATPase with FITC is competitively inhibited by ATP, AMPPNP, TNP-ATP, and less effectively by ADP or ITP the concentrations of the various nucleotides required for protection are consistent with their affinities for the ATP binding site of the Ca -ATPase [114,212,340]. 

Heijn, M., Oude Elferink, R. and Jansen, P. (1992). ATP-dependent multispecific organic anion transport system in rat erythrocyte membrane vesicles. Am. J. Physiol. 262, 104-110. 

Hirohashi, T., et al. ATP-dependent transport of bile salts by rat multidrug resistance-associated protein 3 (Mrp3). J. Biol. Chem. 2000, 275, 2905-2910. 

Fig. 12.2. Comparison of ATP-dependent transport activity between rats and humans determined in isolated bile canalicular membrane vesicles. Key 1, SN-38 glucuronide (carboxylate) 2, SN-38 glucuronide (lactone) 3, E3040 (6-hydroxy-5,7-dimethyl-2-methyl-amino-4-(3-pyridylmethyl) benzothiazole) glucuronide 4, 170 estradiol-170-D-glucuro-nide 5, grepafloxacin glucuronide 6, leuko-...

Doige, C. A., Ames, G. F., ATP-dependent transport systems in bacteria and humans relevance to cystic fibrosis and multidrug resistance, Annu. Rev. Microbiol. 1993, 47, 291-319. 

S. E., Multidrug resistance in cancer role of ATP-dependent transporters, Nature Rev. Cancer 2002, 2, 48—58. 

Muller, M., Mayer, R., Hero, U., Keppler, D., ATP-dependent transport of amphiphilic cations across the hepatocyte canalicular membrane mediated by mdrl P-glycoprotein, FEBS Lett. 1994, 343, 168-172. 

Leier I, Hummel-Eisenbeiss J, Cui Y, Keppler D. ATP-dependent para-amino-hippurate transport by apical multidrug resistance protein MRP2. Kidney Int 2000 57(4) 1636—1642. 

Uchiumi T, Hinoshita E, Haga S, Nakamura T, Tanaka T, Toh S et al. Isolation of a novel human canalicular multispecific organic anion transporter, cMOAT2/MRP3, and its expression in cisplatin-resistant cancer cells with decreased ATP-dependent drug transport. Biochem Biophys Res Commun 1998 252(1)703-110. 

In adult brain most cholesterol synthesis occurs in astrocytes. Apoprotein E (apoE) is the major apolipopro-tein of the CNS and it is secreted by astrocytes. In astrocyte cultures apoE appears in the media as cholesterol-rich particles of a size similar to peripheral HDL (5-12 nm) (Fig. 2-7). The ATP-dependent transporter ABCA1, expressed by both astrocytes and neurons, promotes the formation of the apoE-stabilized high-density lipoprotein (HDL)-sized particles from astrocytic cholesterol. 

ATP-dependent Ca2+ pumps and Na+,Ca2+ antiporters act in concert to maintain a low concentration of free cytosolic Ca2+ 79 The uniquely high resolution structural data available for the SERCAla Ca2+ pump illuminates the structure of all P-type transporters 81 P-type copper transporters are important for neural function 82... 

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